recent modalities in asthma management

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Spot light on recent available and future possible therapies for bronchial asthma

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بسم الله الرحمن الرحيم (( قُلْ هَلْ يَسْتَوِي الَّذِينَ يَعْلَمُونَ وَالَّذِينَ لَا يَعْلَمُونَ إِنَّمَا يَتَذَكَّرُ أُوْلُوا الْأَلْبَابِ )) صدق الله العظيم الزمر۹

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RECENT MODALITIES IN ASTHMA THERAPY By Dr Mahmoud Alsalahy Assist Prof of chest medicine Banha University

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Bronchial asthma is one of the most common chronic diseases and incidence is increasing Now 300 millions, expected 400 millions after 20 yrs worldwide Ranges from 1% to 35% of population with worldwide distribution The incidence is highest in children and decreases with age Asthma constitutes a major public health problem: ○ High cost of medical services ○ 15 million work days are lost / yr worldwide ○ Fatalities still occurring: 0.1-1% of all deaths

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Although cure of asthma is not possible at the present time and no flashing lights for its possibility in the near horizon, the far future may bring a hope…SO, The only hope now is to achieve optimal control

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Despite improvements added to asthma therapy in the last 2 decades, yet about 50% of asthmatics are not controlled Common causes are: Poor patient education Poor patient compliance Poor prescription (6-44%) Side effects of drugs Expensive medications Poor communication Steroid resistance

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So, new modalities are needed to: Improve compliance Decrease cost Decrease side effects Better overall control Control difficult cases Decrease fatalities

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New methods for assessing control New devices for topical drug delivery New drugs: Bronchodilators, Corticosteroids, IgE targeting, Cytokine targeting, Th2 response targeting, Lymphocyte adhesion targeting, Other targets Statins Lipoxins RECENT MDOALITIES OVERVIEW

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Targeting airway remodeling Immunotherapy T cell therapy Gene therapy Overcoming steroid resistance Stem cells and regenerative medicine Nanotechnology RECENT MDOALITIES OVERVIEW

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RECENT METHODS FOR ASSESSING CONTROL

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Currently asthma control is assessed by clinical and physiol. parameters: No day or night symptoms, no or minimal use of rescue medications and with normal activity and lung functions Recently, trends are towards objective confirmation of control of airway inflammation: this can be achieved by direct and indirect methods

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INDIRECT : Measuring airway reactivity: G ood correlation with biopsy changes Eosinophil number in induced sputum: ↓below 3% of pretreatment = control, rise after stopping steroid = liability to exacerbations Exhaled nitric oxide: correlates well with biopsy, almost will be a routine test in near future Analysis of exhaled breath condensate for pH and volatile substances: Still under investigations

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Device for bedside measurement of exhaled NO NIOX®

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DIRECT: Bronchial biopsy: Is the most accurate method for assessing airway inflammation and response to therapy It is invasive and must be done cautiously It will be more safe when done after clinical and non invasive judging of control (Electron Microscopy)

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New therapy guidelines: All new guidelines ( GINA, BTS, ATS, AUTS) stress the stepwise approach as well as patient self management for reaching optimal control

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NEW DEVICES FOR DRUG DELIVERY

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Greatly improve patient compliance Highly active topical drugs can be given Easy use with once or twice daily dosing Combined drugs in one device The SMART use of medications New MDI: the Autohaler: Breath actuated Need no co-ordination Contain HFA as propellant with efficient dosing Mouth piece cover Lever

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Dry powder inhalers: Deliver micronized powder of the drug with: = Easy use = Effective delivery ACUHALER(DISCUS) AEROLIZER SPINHALER TURBOHALER TWISTHALER ROTAHALER

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NEW DRUGS

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NEW BRONCHODILATORS Beta 2 agonists: ultra long acting 24-36 hrs Indacaterol ( Onbrez , breezhaler 150-300µg) Bambuterol ( Bambec , 10-20 mg tab – oral use ) Once daily dosing greatly improve patient compliance Indacaterol Breezhaler

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NEW BRONCHODILATORS contd. Parasympatholytic: ultra long acting Tiotropium (Spiriva, handihaler , 18 µg cap) - Primarily used in COPD but now increasingly used in asthma with good results - Once daily dosing improves compliance Spiriva Handihaler

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NEW BRONCHODILATORS contd. New steroids(soft steroids): Conjugated steroids activated locally Long acting – topically potent- less systemic SEs Mometasone furoate ( Asmanex twisthaler , 110, 220 µg) Ciclesonide ( Alvesco , MDI, 80-160 µg) Rofleponide Loteprednol The last 2 are under clinical studies

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NEW BRONCHODILATORS contd. PDE inhibitors: Non selective: Doxofylline Dioxalan -methyl- theofylline Spares A1& A2 receptors → better safety Selective PDE4 inhibitors: Mesembrine , Rolipram , Ibudilast , Piclamilast , Cilomilast , Luteolin = Effective, generally safe, have anti- inflammatory actions = Cilomilast is the only available now ( Arfillo , 15 mg tab ) twice daily

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ASTHMATIC NON ASTHMATIC Th 2 Th 1

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IgE TARGETING Omalizumab ( Xolair ) : is a recombinant humanized mono-clonal antibody against IgE. Blocks Ag Ab reaction on the surface of mast cells and basophils. Use: ● Poorly controlled ● > 12 yrs old ● High IgE Given by injection: = Available as 150 mg/1.2 mL vial = Dose : 150–375 mg SC every 2 or 4 weeks for 12 inj according to serum IgE and bodyweight (use manufacturer’s dose chart) SEs: expensive, local reaction, anaphylaxis, ↓ anti-tumor & anti-parasite immunity

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CYTOKINE TARGETING IL-4 is a pro-inflammatory cytokine & IL-5 is responsible for Eosinophil growth and maturation Targeting these 2 cytokines can greatly improve asthma control Ultrakincept : Recombinant soluble IL-4 receptor antagonist 1500 µg by nebulizer appear safe and effective for 1 week Mepolizumab : Recombinant m onoclonal ab. against IL-5 Better effect in patients with high eosinophilia Dose: 750 mg/ iv infusion for 3 infusions / 2-3 wks

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Suplatast tosilate : Dimethyl sulphonium compound Selectively inhibits release of Th2 cytokines ( IL-4, IL-5 & IL-13) and IL-13 from basophils Decreases eosinophil no., IgE, CD25 and CD4+ Resquimod : Imidazo - quinoline -amine derivative Inhibits Th2 cell response & ↓ IgE production Has antiviral activity Given orally and by inhalation TARGETING Th2 CELL RESPONSE

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TARGETING LYMPHOCYTE ADHESION Efalizumab : Humanized IgG1 ab. against LFA-1 Inhibits lymphocyte-leukocyte adhesion OTHER TARGETS IDEC-152: Humanized IgG1 ab. Against CD23 CD23 is a low affinity IgE receptor found on lymphocytes, eosinophils, macrophages, platelets Some allergens detach it from cell surfaces Soluble CD23 recruits B lymphocytes → more IgE Recombinant IL-12: Promotes growth & differentiation of Th 1 cells

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STATINS & LIPOXINS Very recently discovered as anti asthma modalities Statins are now under evaluation in asthma therapy by AAAAI It was observed that asthmatics with co-morbidities who are on statins have 30% lower risk for ER visits & hospitalizations due asthma than controls Lipoxins (LXs) are products of the 15 lipo-oxygenase from arachidonic acid LX A4, the main product, is found elevated during resolution from asthma attacks and very low during severe exacerbations LXs have anti IL-8 effects and inhibit Ca ++ influx

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TARGETING AIRWAY REMODELING

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Airway remodeling (thickened SEM & hypertrophied ASM) causes : Anatomical airway narrowing Altered airway geometry twitchy ASM Functional steroid resistance So, targeting remodeling will greatly improve asthma outcome Bronchial thermoplasty has been recently approved by FDA for asthma therapy Poor control

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TARGETING AIRWAY REMODELING contd. Bronchial thermoplasty Concept : Passing RF pulses through the airway tissues generates heat due to tissue resistance debulking of ASM Devices : Alair thermoplasty apparatus and RF compatible FOB Patient selection: Over 18 yrs old On stable maintenance asthma medications Not controlled on ICS alone Stable asthma status No associated comorbid condition that contra-indicates FOB So, full clinical evaluation is needed before the procedure

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The catheter Foot switch 5 mm 1.5 mm RF generator Electric pad (pt body) Electrode array Controller screen Alair system for BT

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Bronchial thermoplasty contd. Patient preparation: 50 mg prednisone /day for 3 days before, the day of and the day after the procedure Moderate sedation Atropine or glycopyrolate Patient must have no cold the day before and the day of the procedure The procedure: 3 sessions 3 wks apart, 1 hr. each 1 st : RLL , 2 nd : LLL , 3 rd both ULs NB. RML not treated ( fear of middle lobe syndrome)

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Procedure 1 Procedure 2 Procedure 3

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Bronchial thermoplasty contd. FOB passed to the area to be treated under clear vision The catheter then passed till appear in vision The electrode array is then expanded till firmly & correctly contact airway wall Predetermined energy doses of RF is then generated by pressing and releasing foot switch Electrodes are then partially collapsed and withdrawn 5 mm proximally for another activation, keeping activation sites contiguous but not overlapping The process is repeated till the entire length of the target airway is completed Before next session the previously treated areas must be healed otherwise postpone

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Bronchial thermoplasty contd. Post procedure: Patient must be observed for 6 hrs post procedure Patient can be discharged if no complications develops Safety and clinical outcome: 4 large clinical trials including 446 patients, followed up for 5 yrs showed : Good safety profile Better outcome in treated patients in terms of control and quality of life All the trials recommended popularization of the procedure

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Pre BT 3 yrs post BT Effect of bronchial thermoplasty in a canine model of asthma ASM ASM Airway biopsy from an asthmatic dog before and 3 yrs after BT

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IMMUNO- THERAPY

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IMMUNOTHERAPY (IT) An old method that recently refined and get great attention Administration of increasing doses of allergen extracts to induce persistent immune tolerance in patients with allergen-induced symptoms. Offers the only ‘curative’ therapy for allergic patients. Is the best line of therapy for allergic rhinitis and is now under re-evaluation in asthma Recently SLIT is preferred for injection SIT and claimed to be more effective in asthma

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Benefits include: ↓ in symptom scores, ↓ in medication usage and ↓ airway reactivity Mechanism: Increased regulatory T cell activity Restoration of Th1- Th 2 balance Switching of allergen-specific B cells towards IgG4 production. Usual course: 3-5 years on maintenance therapy (not settled for SLIT) It is safe in pregnancy IMMUNOTHERAPY contd.

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IMMUNOTHERAPY contd. Recent methods for IT Allergen peptides: The active peptides of allergens are used → down regulation of T cells without co-stimulatory signals 2 refinements: Short T cell epitope peptides: induce tolerance without mediator release (no IgE binding) B cell epitope derived peptides: stimulate B cells to produce blocking IgG 1 without IgE binding Recombinant allergens: Reconstructed with reduced allergenic activity Different IgE epitope conformation reduced IgE binding

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IMMUNOTHERAPY contd. CpG -DNA based immunotherapy: Giving cytosine guanine plasmid DNA with allergen extract produce a strong Th-1 response with increase of mucosal IF- ϒ and decrease IgE production

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T CELL THERAPY

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Cloned Th -1 cells are now under trials and promising results obtained Aim: correction of Th1-Th2 imbalance in asthma with correction of cytokine profile: ↑↑ IL-1, IL-12, IF- ϒ & ↓↓ IL-4, IL-5, IL-13

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GENE THERAPY

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Is the insertion of a functional gene in a target cell to exert the gene function Genes transferred to target cells by a viral vector or a liposome (? nanocarrier ) Target cells in the lungs are respiratory epithelium Cytokine encoding genes: Genes encoding for IL-12, IF- ϒ , IL-18: Cause marked reduction in eosinophilic inflammation, IgE production and airway hyperresponsiveness Genes encoding for IL-10 and TGF- β : Cause suppression of both Th-1&Th-2 response

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STAT-6 gene Sends signal to the nucleus to produce IL-4 RNA and targeting this gene can suppress IL-4 formation β 2 receptors encoding genes: To over express β 2 receptors and potentiate bronchodilation 21-mer gene: Encodes for A1 receptors antagonist protein Gob-5 gene: Encodes for Ca ++ dependent Cl - channel in airway epith . and greatly decreases airway hyperreactivity Glucocorticoid R genes: Over expression overcomes GCR resistance and decrease systemic SEs GENE THERAPY contd.

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OVERCOMING STEROID RESISTANCE

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Corticosteroids are the main stay in asthma management About 5-10% of asthmatics are resistant to steroids 90% of this resistance is functional and can be corrected High levels of IL-2 & IL-4 as well as airway remodeling are the main causes IL-2 & IL-4 levels can be lowered by IV immunoglobulins: 2-3 mg / kg / wk / 4wks Bronchial thermoplasty offers a hope to overcome remodeling

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STEM CELL AND REGENERATIVE MEDICINE

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Regenerative medicine and stem cell technology is under extensive research to find a solution for many incurable diseases Bronchial asthma is one of such diseases waiting in the list Animal experiments are very appointing Asthma model in mice sensitized to ragweed showed great reduction of their allergic manifest- ations after iv injection of bone marrow stem cells The mechanism is not clear , but the authors supposed ( lymphocyte balance) as the working one

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NANO- TECHNOLGY

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Nanotechnology opens a wide door on future medicine and it is hoped to solve many unsolved medical problems Development of biodegradable nanoparticles encouraged research on respiratory diseases Itraconazol nanoparticles given by inhalation effectively controlled growth of Aspergillus than oral route in allergic aspergellosis

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Chitosan ( a cationic natural biopolymer produced by the alkaline N - deacetylation of chitin) nanoparticles are used as: Gene vector with efficient transfer of: IF- ϒ cloned DNA to respiratory epith . with marked attenuation of allergic inflammation in mice siRNA against specific viral antigens carried by chitosan nanoparticles and given intra-nasally protected against RSV Drug carrier: T heophylline given coated on chitosan nanoparticles intra nasally has effective bronchodilatation and anti-inflammatory effect with low serum levels and SEs

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Science, specially medicine, is continuously changing with new ideas, thoughts and applications every day So, we hope in future that some of such ideas or applications aid in solving the problem of bronchial asthma

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Thank You